Piperidino or morpholino-2-phenyl-2-cyano-butyl urethanes

ABSTRACT

IN WHICH R IS A STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 6 CARBON ATOMS; R1 IS A STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 6 CARBON ATOMS, PHENYL, OR PHENYL MONO- OR DISUBSTITUTED BY HALOGEN, TRIFLUORMETHYL, NITRO, ALKYL OF 1 TO 3 CARBON ATOMS OR ALKOXY OF 1 TO 3 CARBON ATOMS; R AND R1 TOGETHER ARE DIVALENT ALKYLEN OF 3 TO 5 CARBON ATOMS; AND NR2 STANDS FOR PIPERIDINO OR MORPHOLINO.   (R)2-N-COO-CH2-C&lt;(-R1-R-)-CN   URETHANES HAVING UTILITY AS MUSCLE-RELAXANTS, ANTISPASMODICS, TRANQUILIZERS AND SEDATIVES AND HAVING THE FORMULA

3,600,387 Patented Aug. 17, I971 3,600,387 PIPERIIDINO RMORPHOLINO-Z-PHENYL-Z- CYA'NO-BUTYL URETHANES Laszlo Suranyi, Mannheim,Germany, assignor to Knoll A.G., Ludwigshafen (Rhine), Germany NoDrawing. Original application Dec. 27, 1966, Ser. No. 604,638, nowPatent No. 3,506,702, dated Apr. 14, 1070. Divided and this applicationJuly 2, 1969, Ser- No. 869,981

Claims priority, applicatigingrmany, Jan. 3, 1966,

U.S. Cl. 260247.2 2 Claims ABSTRACT OF THE DISCLOSURE Urethanes havingutility as muscle-relaxants, antispasmodics, tranquilizers and sedativesand having the formula in which R is a straight or branched chain alkylof 1 to 6 carbon atoms; R is a straight or branched chain alkyl of 1 to6 carbon atoms, phenyl, or phenyl monoor disubstituted by halogen,trifluoromethyl, nitro, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3carbon atoms; R and R together are divalent alkylene of 3 to 5 carbonatoms; and NR stands for piperidino or morpholino.

This application is a division of copending application Ser. No.604,638, filed Dec. 27, 1966, now U.S. Pat. 3,506,702.

This invention relates to novel urethanes of the formula in which R is astraight or branched chain alkyl of 1 to 6 carbon atoms; R is a straightor branched chain alkyl of 1 to 6 carbon atoms, phenyl, or phenyl monoordisubstituted by halogen, trifluoromethyl, nitro, alkyl of l to 3 carbonatoms or alkoxy of 1 to 3 carbon atoms;

R and R together are divalent alkylene of 3 to 5 carbon atoms; R; and Rare hydrogen, lower alkyl, lower alkoxy or benzyl; and R and R togetherwith the nitrogen stand for a six-membered heterocyclic ring, and to amethod for preparing and administering such urethanes. The compounds ofthe invention are obtainable by reacting 0L,Ot-diSl.lbStitlltCdfi-hydroxypropionitriles of the formula R1 R-( J-CHzOH ('JN II with:

(A) carbamic acid esters of low molecular weight aliphatic alcohols inthe presence of reesterification catalysts such as aluminumisopropylate, sodium alcoholate and magnesium alcoholate;

(B) chloroformic acid esters followed by reaction of the resultingproduct with an amine of the formula (C) phosgene and reacting theresulting chloroformic acid ester with an amine of Formula III.

Chloroformic acid phenyl esters are preferred as reactants in embodimentB. Reaction of the chloroformic acid esters with the propionitriles ofFormula II is ad vantageously carried out in the presence of pyridine orother tertiary base. Also in the subsequent reaction of the neutralcarbonic acid ester formed in the first step with amines of Formula II,the presence of basic condensation agents such as tertiary bases or theuse of an excess of the amine component is recommended.

In embodiment C, phosgene is led into a propionitrile of Formula II atambient temperature or moderately elevated temperature. Thepropionitrile can be used as such or in an aromatic hydrocarbon solventsuch as toluene, benzene or xylene. The subsequent reaction of theresulting chloroformic acid ester with an amine of Formula III takesplace under the same conditions as in embodiment B of the process.

The starting materials represented by Formula II are obtainable bycondensation of the corresponding substituted phenylacetonitriles withformaldehyde in the presence of strongly basic condensing agents such asbenzyltrimethylammonium hydroxide in solvents such as pyridine. They arealso obtainable by reduction of the. corresponding cyanacetic acidesters with complex metal hydrides under conditions favoring reductionof the ester group. The starting materials are mostly highly viscousoils.

The compounds of the invention are capable of exerting a depressiveeifect on the central nervous system. They have prolongedmuscle-relaxing and anti-spasmodic activity and are useful astranquilizing agents and sedatives.

In comparison with some of the known compounds having similar activity,the compounds of the invention compare most favorably. Thus, forexample, ot-phenyl-txcyano-butylurethane has a stronger sedative actionthan hydroxyphenamate and has a stronger muscle-relaxant activity thanhydroxyphenamate and meprobamate. Another compound, at p chlorophenyl acyano butylurethane, is considerably superior to hydroxyphenamate inantispasmodic activity. It is approximately equivalent to sodiumphenobarbital in sedative activity, although much greater doses arerequired to initiate narcotic activity, and is very much less toxic thanphenobarbital and meprobamate.

Individual therapeutic dosages are preferably of the order of 100 to 200mg. per os; daily therapeutic dosages are about 300 to 600 mg. per 0s.The compounds of the invention may be admixed and dispensed withsuitable carrier materials well-known to those skilled in the art.

The following examples are included to illustrate the invention.

EXAMPLE 1 2- (4-tolyl)-2-cyano-butylurethane 94.5 g. of2-ethyl-2-(4-tolyl)-3-hydroxypropionitrile (M.P. 76 C.) are subjected toazeotropic distillation in a column with 111.5 g. ethylurethane, 25 g.aluminum isopropylate in 1 l. cycloheXane. The alcohol-cyclohexaneazeotrope is removed from the head of the column and the cyclohexane isreplaced continuously at the rate of 4 The same procedure was followedin Examples 10 to 21 below. Any final product not obtained incrystalline form was purified chromatographically.

withdrawal. When the re-esterification is complete, the 5 Ex. Final podu t M-P-,O. corftentiof column are evagorated to drynfiss, h l 2pcl1loropl1enyLZ-cyanwbutylurcthane 99-101 residue is dissolved in 100 ml.lsopropanol and, while Z wY Z-WM u isgu t an 33:3?

p eny- CyfiIlO-ISOBJIIY are 3.118...." stirrmg and cooling, added to 1l. of 0.5 N hydrochloric 2 pheny1 2 cyam isohexylurethane n H8 acid.After some time, 2-(4- -tolyl)-2-cyano-butylurethane fin gpyl-grcyano(BKm E Y gYD- thanm p eny- -cyano-nexy ure ane crystallizes 1nthe form of fine needles, wh1ch are filtered 1O henl-a-cyano-propylurethane 77-79 011, dried, and recrystallized frombenzene-lrgrom. The g-prnftgoxylgkhenylfi-cyafiugbutylurethania th 22; oirneoxyp cny -cyanoisoarny ure ane 8 Yleld 1S the meltmg P 18 192-(3,4-dimethoxyphenyl)-2-cyanobutylurethane 117-11s.5 The sameprocedure was followed in Examples 2 to 20. y p y y 0 u y u t a 6 8below. Any final product not obtained in crystallinewmtmphenyl'2cyan'butylumthane 99400 form was purifiedchromatographically. Highly viscous oil.

Example Starting material Final product M.P C.

2 2-ethyl-2-(3-tolyl)-3-hydroxypropionitri1e2-(3-tolyl)-2-cyano-butylurethane 82-832-ethyl-2-(3',4-xylyl)-3-hydroxypropionitrile2-(3,4-xylyl)-2-cyano-butylurethane 119-1212-ethyl-2-isopropyl-3-hydroxypr0pionit1'ile2-isopropyl-Z-cyano-butylurethane 72. 5-742-ethyl-2(1-methylbutyl)-3-hydr0xypropionitr1le.2-(1-methylbutyl)-2-cyano-butylurethane1-cyano-1-hydroxymethylcyclopentane l-cyano-cyclopentylmethy1urethane57-60 7 2-ethyl-2-isoamyl-3-hydroxypropionitrile 8 2-ethyl'2'sec.butyl-3-hydroxypropionitrile 2-sec. butyl-Z-cyano-butylurethane 1Viscous oil.

EXAMPLE 9 2-phenyl-2-cyano-butylurethane A similar procedure was used inExamples 22 to 30, below, to obtain N-substituted urethanes by reactionof the corresponding 2,2 disubstituted 3 hydroxypropionitrilecarbonicacid phenyl esters with primary or secondary amines of Formula III.

Ex. Final product B.P. mm./ O.) M.P., C.

22 N-butyl-2-phcnyl-2-cyanobutylurethane 0. 01/ 160-180 N,N-dimethyl-Z-pheny1-2-cyano-butylurethane 0. 1 130. 150

N-pentarnethylene-2-phanyl-2-cyano-butylurethanc 0. 1/ 150-170Morphollno-carbonic acid ester of 2-pheny1-2-cyanobutylalcohol 0.01/160-180 N-methyl-2-p-chlorophenyl-Z-cyano-butylu.rethane 69-71 N,N-dimethyl'2-p-chlorophenyl-Z-cyanobutylurethane 0. 01/100-180 N-isopropyl-Z-p-chloro ph enyl-Z-cyano -butylurethane 70-72N-hydroxyethyl-Z-p-chlorophenyl-2-cyano-bntylurethaneN-benzyl-Z-p-ehlorophenyl-Z-cyano-butylurethanc I claim: 1.N-pentamethylene-Z-phenyl-2-cyanobutylurethane. 2. Morpholino-carbonicacid ester of 2-phenyl-2-cyanobutyl alcohol.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R.

zoo-294.3, 465

